tbuckley/cabot-search huggingface dataset:
Using historical objective response rates to design single-arm phase II trials in patients with recurrent glioblastoma
Authors: Stuart A Grossman
Journal: Neuro-Oncology (2023)

Journal Article Using historical objective response rates to design single-arm phase II trials in patients with recurrent glioblastoma Get access Stuart A Grossman Stuart A Grossman Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA Corresponding Author: Stuart A. Grossman, MD, Johns Hopkins University School of Medicine, Baltimore, MD, USA (grossman@jhmi.edu). https://orcid.org/0000-0002-3726-7679 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 6, June 2023, Pages 1029–1030, https://doi.org/10.1093/neuonc/noad046 Published: 07 March 2023 Article history Published: 07 March 2023 Corrected and typeset: 16 March 2023
MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis
Authors: John Mascarenhas, Marina Kremyanskaya, Andrea Patriarca, Francesca Palandri, Timothy Devos, Francesco Passamonti, Raajit K. Rampal, Adam J. Mead, Gabriella Hobbs, Joseph M. Scandura, Moshe Talpaz, Nikki Granacher, Tim C. P. Somervaille, Ronald Hoffman, Marielle J. Wondergem, Mohamed E. Salama, Gozde Colak, Jike Cui, Jean-Jacques Kiladjian, Alessandro M. Vannucchi, Srdan Verstovsek, Natalia Curto-García, Claire Harrison, Vikas Gupta
Journal: Journal of Clinical Oncology (2023)

PURPOSE Standard therapy for myelofibrosis comprises Janus kinase inhibitors (JAKis), yet spleen response rates of 30%-40%, high discontinuation rates, and a lack of disease modification highlight an unmet need. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). METHODS MANIFEST (ClinicalTrails.gov identifier: NCT02158858 ), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. The primary end point is a spleen volume reduction of ≥ 35% (SVR35) at 24 weeks. RESULTS Eighty-four patients received ≥ 1 dose of pelabresib and ruxolitinib. The median age was 68 (range, 37-85) years; 24% of patients were intermediate-1 risk, 61% were intermediate-2 risk, and 16% were high risk as per the Dynamic International Prognostic Scoring System; 66% (55 of 84) of patients had a hemoglobin level of &lt; 10 g/dL at baseline. At 24 weeks, 68% (57 of 84) achieved SVR35, and 56% (46 of 82) achieved a total symptom score reduction of ≥ 50% (TSS50). Additional benefits at week 24 included 36% (29 of 84) of patients with improved hemoglobin levels (mean, 1.3 g/dL; median, 0.8 g/dL), 28% (16 of 57) with ≥ 1 grade improvement in fibrosis, and 29.5% (13 of 44) with &gt; 25% reduction in JAK2V617F-mutant allele fraction, which was associated with SVR35 response ( P = .018, Fisher's exact test). At 48 weeks, 60% (47 of 79) of patients had SVR35 response. Grade 3 or 4 toxicities seen in ≥ 10% patients were thrombocytopenia (12%) and anemia (35%), leading to treatment discontinuation in three patients. 95% (80 of 84) of the study participants continued combination therapy beyond 24 weeks. CONCLUSION The rational combination of the BETi pelabresib and ruxolitinib in JAKi-naïve patients with myelofibrosis was well tolerated and showed durable improvements in spleen and symptom burden, with associated biomarker findings of potential disease-modifying activity.
“Time” for obesity-related cancer: The role of the circadian rhythm in cancer pathogenesis and treatment
Authors: Caterina Miro, Annamaria Docimo, Luigi Barrea, Ludovica Verde, Simona Cernea, Antoan Stefan Sojat, Ljiljana V. Marina, Giovanni Docimo, Annamaria Colao, Monica Dentice, Giovanna Muscogiuri
Journal: Seminars in Cancer Biology (2023)

The circadian rhythm is regulated by an intrinsic time-tracking system, composed both of a central and a peripheral clock, which influences the cycles of activities and sleep of an individual over 24 h. At the molecular level, the circadian rhythm begins when two basic helix-loop-helix/Per-ARNT-SIM (bHLH-PAS) proteins, BMAL-1 and CLOCK, interact with each other to produce BMAL-1/CLOCK heterodimers in the cytoplasm. The BMAL-1/CLOCK target genes encode for the repressor components of the clock, cryptochrome (Cry1 and Cry2) and the Period proteins (Per1, Per2 and Per3). It has been recently demonstrated that the disruption of circadian rhythm is associated with an increased risk of developing obesity and obesity-related diseases. In addition, it has been demonstrated that the disruption of the circadian rhythm plays a key role in tumorigenesis. Further, an association between the circadian rhythm disruptions and an increased incidence and progression of several types of cancer (e.g., breast, prostate, colorectal and thyroid cancer) has been found. As the perturbation of circadian rhythm has adverse metabolic consequences (e.g., obesity) and at the same time tumor promoter functions, this manuscript has the aim to report how the aberrant circadian rhythms affect the development and prognosis of different types of obesity-related cancers (breast, prostate, colon rectal and thyroid cancer) focusing on both human studies and on molecular aspects.
Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs
Authors: Zhiwen Li, Zhihao Guo, Xi Lu, Xican Ma, Xiukun Wang, Rui Zhang, Xinxin Hu, Yanxiang Wang, Jing Pang, Tianyun Fan, Yonghua Liu, Sheng Tang, Haigen Fu, Jingpu Zhang, Yinghong Li, Xuefu You, Danqing Song
Journal: Acta Pharmaceutica Sinica B (2023)

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4–512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.
Efficacy and safety of gluten peptide-based antigen-specific immunotherapy (Nexvax2) in adults with coeliac disease after bolus exposure to gluten (RESET CeD): an interim analysis of a terminated randomised, double-blind, placebo-controlled phase 2 study
Authors: Jason A Tye-Din, A James M Daveson, Gautam Goel, Kaela E Goldstein, Holly L Hand, Kristin M Neff, Alina Popp, Juha Taavela, Markku Maki, Jorma Isola, Leslie J Williams, Kenneth E Truitt, Robert P Anderson, Atoya Adams, Jane M Andrews, Clint E Behrend, Gregor J E Brown, Swee Lin Chen Yi Mei, Allan G Coates, Anthony J DiMarino, Hooi Ee, David E Elliott, Roger M Epstein, Bryan John Feyen, Ronald P Fogel, Keith Alan Friedenberg, Richard B Gearry, Michael S Gerdis, Michael J Goldstein, Vipin K Gupta, Robert John Holmes, Gerald J Holtmann, Samuel H Idarraga, George W James, Tim King, Terry D Klein, Sonia S Kupfer, Benjamin Lebwohl, Matthew John Lowe, Joseph A Murray, Eric B Newton, Dean Quinn, David M Radin, Timothy E Ritter, Helen Lee Stacey, Cynthia B Strout, Richard S Stubbs, Susan Lynn Thackwray, Vivek M Trivedi, John R Weber, Scott A Wilson
Journal: The Lancet. Gastroenterology & hepatology (2023)
Massive Somatic and Germline Chromosomal Integrations of Polydnaviruses in Lepidopterans
Authors: Camille Heisserer, Héloïse Muller, Véronique Jouan, Karine Musset, Georges Periquet, Jean-Michel Drezen, Anne-Nathalie Volkoff, Clément Gilbert
Journal: Molecular Biology and Evolution (2023)

Abstract Increasing numbers of horizontal transfer (HT) of genes and transposable elements are reported in insects. Yet the mechanisms underlying these transfers remain unknown. Here we first quantify and characterize the patterns of chromosomal integration of the polydnavirus (PDV) encoded by the Campopleginae Hyposoter didymator parasitoid wasp (HdIV) in somatic cells of parasitized fall armyworm (Spodoptera frugiperda). PDVs are domesticated viruses injected by wasps together with their eggs into their hosts in order to facilitate the development of wasp larvae. We found that six HdIV DNA circles integrate into the genome of host somatic cells. Each host haploid genome suffers between 23 and 40 integration events (IEs) on average 72 h post-parasitism. Almost all IEs are mediated by DNA double-strand breaks occurring in the host integration motif (HIM) of HdIV circles. We show that despite their independent evolutionary origins, PDV from both Campopleginae and Braconidae wasps use remarkably similar mechanisms for chromosomal integration. Next, our similarity search performed on 775 genomes reveals that PDVs of both Campopleginae and Braconidae wasps have recurrently colonized the germline of dozens of lepidopteran species through the same mechanisms they use to integrate into somatic host chromosomes during parasitism. We found evidence of HIM-mediated HT of PDV DNA circles in no less than 124 species belonging to 15 lepidopteran families. Thus, this mechanism underlies a major route of HT of genetic material from wasps to lepidopterans with likely important consequences on lepidopterans.
Safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster following three doses of CoronaVac: a multicentre, open-label, phase 4, randomised trial
Authors: Rong Tang, Hui Zheng, Bu-Sen Wang, Jin-Bo Gou, Xi-Ling Guo, Xiao-Qin Chen, Yin Chen, Shi-Po Wu, Jin Zhong, Hong-Xing Pan, Jia-Hong Zhu, Xiao-Yu Xu, Feng-Juan Shi, Zhuo-Pei Li, Jing-Xian Liu, Xiao-Yin Zhang, Lun-Biao Cui, Zhi-Zhou Song, Li-Hua Hou, Feng-Cai Zhu, Jing-Xin Li, Hai-Tao Huang, Xiao-Long Li, Xue Wang, Peng Wan, Tao Zhu
Journal: The Lancet Respiratory Medicine (2023)
NanoString analysis of mycosis fungoides reveals individual molecular identity
Authors: Ruth Alonso-Alonso, Marta Rodríguez, Nuria García-Díaz, Laura Tomás-Roca, Jennifer  Borregón, Marta Cabezuelo-Rodríguez, Marcos Rebollo-González, Luis Gallego-Manzano, Laura Cereceda, Socorro María Rodriguez-Pinilla, Raúl Córdoba, Juan Fernando García, Juan Torre-Castro, Carmen M García-Álvarez, María del Mar Onteniente Gomis, Raquel Rivera-Díaz, José Luis Rodriguez-Peralto, José Pedro Vaqué, Pablo Luis Ortiz-Romero, Miguel Á Piris
Journal: British Journal of Dermatology (2023)

Gene profiling using a customized NanoString platform can be applied to routine mycosis fungoides (MF) samples, revealing their specific molecular features. This study shows that MF samples carry a signature derived from individual molecular features found in consecutive biopsies.
SARS-CoV-2 omicron (B.1.1.529)-related COVID-19 sequelae in vaccinated and unvaccinated patients with cancer: results from the OnCovid registry
Authors: Alessio Cortellini, Josep Tabernero, Uma Mukherjee, Ramon Salazar, Anna Sureda, Clara Maluquer, Daniela Ferrante, Mark Bower, Rachel Sharkey, Oriol Mirallas, Andrea Plaja, Marc Cucurull, Ricard Mesia, Alessia Dalla Pria, Thomas Newsom-Davis, Mieke Van Hemelrijck, Ailsa Sita-Lumsden, Eleanor Apthorp, Bruno Vincenzi, Giuseppina Rita Di Fazio, Giuseppe Tonini, Francesco Pantano, Alexia Bertuzzi, Sabrina Rossi, Joan Brunet, Matteo Lambertini, Paolo Pedrazzoli, Federica Biello, Francesca D'Avanzo, Alvin J X Lee, Marianne Shawe-Taylor, Lucy Rogers, Cian Murphy, Lee Cooper, Ramis Andaleeb, Saira Khalique, Samira Bawany, Sarah Ahmed, M Carmen Carmona-García, Roser Fort-Culillas, Raquel Liñan, Federica Zoratto, Gianpiero Rizzo, Marta Perachino, Kris Doonga, Gianluca Gaidano, Riccardo Bruna, Andrea Patriarca, Clara Martinez-Vila, Ignacio Pérez Criado, Raffaele Giusti, Francesca Mazzoni, Lorenzo Antonuzzo, Armando Santoro, Alessandro Parisi, Paola Queirolo, Avinash Aujayeb, Lorenza Rimassa, Nikolaos Diamantis, Rossella Bertulli, Claudia A M Fulgenzi, Antonio D'Alessio, Isabel Ruiz-Camps, Nadia Saoudi-Gonzalez, David Garcia Illescas, Irene Medina, Laura Fox, Alessandra Gennari, Juan Aguilar-Company, David J Pinato, Joanne S Evans, Judith Swallow, Georgina Hanbury, Chris Chung, Meera Patel, Gino Dettorre, Katherine Belessiotis, Dolly Saorise, Eleanor Jones, Eleanor Apthorp, Charlotte Moss, Beth Russell, Sarah Townsend, Amanda Jackson, Angela Loizidou, Martine Piccart, Fanny Pommeret, Emeline Colomba-Blameble, Aleix Prat, Claudia A Cruz, Roxana Reyes, Elia Segui, Javier Marco-Hernández, Margarita Viladot, Nadia Harbeck, Rachel Wuerstlein, Franziska Henze, Sven Mahner, Eudald Felip, Lorenza Scotti, Andrea Marrari, Federica Grosso, Vittorio Fusco, Sara Delfanti, Maura Rossi, Alberto Zambelli, Carlo Tondini, Lorenzo Chiudinelli, Michela Franchi, Michela Libertini, Salvatore Provenzano, Daniele Generali, Salvatore Grisanti, Alice Baggi, Valeria Tovazzi, Corrado Ficorella, Giampiero Porzio, Maristella Saponara, Marco Filetti, Marco Tucci, Rossana Berardi, Luca Cantini, Francesco Paoloni, Annalisa Guida, Sergio Bracarda, Maria Iglesias, Ana Sanchez de Torre, Marco Tagliamento
Journal: The Lancet Oncology (2023)
Endoscopic removal of lumen-apposing metal stents – risk factors for stent embedment, complex removals, and adverse events: analysis from a multicenter prospective case series
Authors: Sergio Bazaga, Francisco Javier García-Alonso, Jose Ramon Aparicio Tormo, Belen Martinez Moreno, Vicente Sanchiz, Carles Suria, Albert Garcia-Sumalla, Joan B. Gornals, Carlos Chavarría, Carme Loras, Francisco Jose García-Fernandez, Álvaro Terán, Enrique Vazquez-Sequeiros, Rafael Pedraza Sanz, Leticia Pérez-Carazo, José Carlos Súbtil, Antonio Pérez-Millan, Francisco Uceda Porta, Victoria Busto Bea, Carlos de la Serna-Higuera, Isabel Pinto Garcia, Juan Colán-Hernández, Carlos Huertas, Carlos Guarner-Argente, Manuel Perez-Miranda
Journal: Endoscopy (2023)

Abstract Background Removing lumen-apposing metal stents (LAMSs) may be difficult and even harmful, but these features have seldom been analyzed. We aimed to generate a comprehensive assessment of the feasibility and safety of LAMS retrieval procedures. Methods A prospective multicenter case series including all technically successfully deployed LAMSs between January 2019 and January 2020 that underwent endoscopic stent removal. All retrieval-related data were prospectively recorded using standardized telephone questionnaires as part of centralized follow-up that ended after stent removal had been performed. Multivariable logistic regression models assessed the potential risk factors for complex removal. Results For the 407 LAMSs included, removal was attempted in 158 (38.8 %) after an indwell time of 46.5 days (interquartile range [IQR] 31–70). The median (IQR) removal time was 2 (1–4) minutes. Removal was labelled as complex in 13 procedures (8.2 %), although advanced endoscopic maneuvers were required in only two (1.3 %). Complex removal risk factors were stent embedment (relative risk [RR] 5.84, 95 %CI 2.14–15.89; P = 0.001), over-the-wire deployment (RR 4.66, 95 %CI 1.60–13.56; P = 0.01), and longer indwell times (RR 1.14, 95 %CI 1.03–1.27; P = 0.01). Partial and complete embedment were observed in 14 (8.9 %) and five cases (3.2 %), respectively. The embedment rate during the first 6 weeks was 3.1 % (2/65), reaching 15.9 % (10/63) during the following 6 weeks (P = 0.02). The adverse event rate was 5.1 %, including seven gastrointestinal bleeds (5 mild, 2 moderate). Conclusions LAMS removal is a safe procedure, mostly requiring basic endoscopic techniques attainable in conventional endoscopy rooms. Referral to advanced endoscopy units should be considered for stents with known embedment or long indwell times, which may require more technically demanding procedures.
Impact of age at diagnosis, sex, and immunopathological manifestations in 886 patients with pediatric chronic immune thrombocytopenia
Authors: Thomas Pincez, Helder Fernandes, Marlène Pasquet, Wadih Abou Chahla, Jérome Granel, Sébastien Héritier, Mony Fahd, Stéphane Ducassou, Caroline Thomas, Nathalie Garnier, Vincent Barlogis, Eric Jeziorski, Sophie Bayart, Pascal Chastagner, Nathalie Cheikh, Corinne Guitton, Catherine Paillard, Julien Lejeune, Frédéric Millot, Valérie Li‐Thiao Te, Coralie Mallebranche, Isabelle Pellier, Bénédicte Neven, Corinne Armari‐Alla, Liana Carausu, Christophe Piguet, Joy Benadiba, Claire Pluchart, Jean‐Louis Stephan, Marianna Deparis, Claire Briandet, Eric Doré, Aude Marie‐Cardine, Thierry Leblanc, Guy Leverger, Nathalie Aladjidi
Journal: American Journal of Hematology (2023)

Pediatric chronic immune thrombocytopenia (cITP) is a heterogeneous condition in terms of bleeding severity, second-line treatment use, association with clinical and/or biological immunopathological manifestations (IMs), and progression to systemic lupus erythematosus (SLE). No risk factors for these outcomes are known. Specifically, whether age at ITP diagnosis, sex, or IMs impact cITP outcomes is unknown. We report the outcomes of patients with pediatric cITP from the French nationwide prospective cohort OBS'CEREVANCE. We used multivariate analyses to investigate the effect of age at ITP diagnosis, sex, and IMs on cITP outcomes. We included 886 patients with a median (min-max) follow-up duration of 5.3 (1.0-29.3) years. We identified an age cutoff that dichotomized the risk of the outcomes and defined two risk groups: patients with ITP diagnosed <10 years (children) and ≥ 10 years (adolescents). Adolescents had a two to four-fold higher risk of grade ≥3 bleeding, second-line treatment use, clinical and biological IMs, and SLE diagnosis. Moreover, female sex and biological IMs were independently associated with higher risks of biological IMs and SLE diagnosis, second-line treatment use, and SLE diagnosis, respectively. The combination of these three risk factors defined outcome-specific risk groups. Finally, we showed that patients clustered in mild and severe phenotypes, more frequent in children and adolescents, respectively. In conclusion, we identified that age at ITP diagnosis, sex, and biological IMs impacted the long-term outcomes of pediatric cITP. We defined risk groups for each outcome, which will help clinical management and further studies.
Chemical exposures and suspected impact on Gulf War Veterans
Authors: Rami Elhaj, Joseph M. Reynolds
Journal: Military Medical Research (2023)

Abstract Gulf War Illness (GWI) encompass a spectrum of maladies specific to troops deployed during the Persian Gulf War (1990–1991). There are several hypothesized factors believed to contribute to GWI, including (but not limited to) exposures to chemical agents and a foreign environment (e.g., dust, pollens, insects, and microbes). Moreover, the inherent stress associated with deployment and combat has been associated with GWI. While the etiology of GWI remains uncertain, several studies have provided strong evidence that chemical exposures, especially neurotoxicants, may be underlying factors for the development of GWI. This mini style perspective article will focus on some of the major evidence linking chemical exposures to GWI development and persistence decades after exposure.
PD-1 blockade plus chemoradiotherapy as preoperative therapy for patients with BRPC/LAPC: A biomolecular exploratory, phase II trial
Authors: Juan Du, Changchang Lu, Liang Mao, Yahui Zhu, Weiwei Kong, Shanshan Shen, Min Tang, Shanhua Bao, Hao Cheng, Gang Li, Jun Chen, Qi Li, Jian He, Aimei Li, Xin Qiu, Qing Gu, Dongsheng Chen, Chuang Qi, Yunjie Song, Xiaoping Qian, Lei Wang, Yudong Qiu, Baorui Liu
Journal: Cell Reports Medicine (2023)

This is a phase II study of PD-1 blockade plus chemoradiotherapy as preoperative therapy for patients with locally advanced or borderline resectable pancreatic cancer (LAPC or BRPC, respectively). Twenty-nine patients are enrolled in the study. The objective response rate (ORR) is 60%, and the R0 resection rate is 90% (9/10). The 12-month progression-free survival (PFS) rate and 12-month overall survival (OS) rate are 64% and 72%, respectively. Grade 3 or higher adverse events are anemia (8%), thrombocytopenia (8%), and jaundice (8%). Circulating tumor DNA analysis reveals that patients with a >50% decline in maximal somatic variant allelic frequency (maxVAF) between the first clinical evaluation and baseline have a longer survival outcome and a higher response rate and surgical rate than those who are not. PD-1 blockade plus chemoradiotherapy as preoperative therapy displays promising antitumor activity, and multiomics potential predictive biomarkers are identified and warrant further verification.
Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice
Authors: Rebecca Jarvis, Shu Fun Josephine Ng, Anna J. Nathanson, Ross A. Cardarelli, Krithika Abiraman, Fergus Wade, Aidan Evans-Strong, Marina P. Fernandez-Campa, Tarek Z. Deeb, Joshua L. Smalley, Tanguy Jamier, Ian K. Gurrell, Lisa McWilliams, Aarti Kawatkar, Leslie C. Conway, Qi Wang, Roland W. Burli, Nicholas J. Brandon, Iain P. Chessell, Aaron J. Goldman, Jamie L. Maguire, Stephen J. Moss
Journal: Cell Reports Medicine (2023)

Hyperpolarizing GABAAR currents, the unitary events that underlie synaptic inhibition, are dependent upon efficient Cl− extrusion, a process that is facilitated by the neuronal specific K+/Cl− co-transporter KCC2. Its activity is also a determinant of the anticonvulsant efficacy of the canonical GABAAR-positive allosteric: benzodiazepines (BDZs). Compromised KCC2 activity is implicated in the pathophysiology of status epilepticus (SE), a medical emergency that rapidly becomes refractory to BDZ (BDZ-RSE). Here, we have identified small molecules that directly bind to and activate KCC2, which leads to reduced neuronal Cl− accumulation and excitability. KCC2 activation does not induce any overt effects on behavior but prevents the development of and terminates ongoing BDZ-RSE. In addition, KCC2 activation reduces neuronal cell death following BDZ-RSE. Collectively, these findings demonstrate that KCC2 activation is a promising strategy to terminate BDZ-resistant seizures and limit the associated neuronal injury.
Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells
Authors: Inge van der Werf, Phoebe K. Mondala, S. Kathleen Steel, Larisa Balaian, Luisa Ladel, Cayla N. Mason, Raymond H. Diep, Jessica Pham, Jacqueline Cloos, Gertjan J.L. Kaspers, Warren C. Chan, Adam Mark, James J. La Clair, Peggy Wentworth, Kathleen M. Fisch, Leslie A. Crews, Thomas C. Whisenant, Michael D. Burkart, Mary E. Donohoe, Catriona H.M. Jamieson
Journal: Cell Reports Medicine (2023)

Pediatric acute myeloid leukemia (pAML) is typified by high relapse rates and a relative paucity of somatic DNA mutations. Although seminal studies show that splicing factor mutations and mis-splicing fuel therapy-resistant leukemia stem cell (LSC) generation in adults, splicing deregulation has not been extensively studied in pAML. Herein, we describe single-cell proteogenomics analyses, transcriptome-wide analyses of FACS-purified hematopoietic stem and progenitor cells followed by differential splicing analyses, dual-fluorescence lentiviral splicing reporter assays, and the potential of a selective splicing modulator, Rebecsinib, in pAML. Using these methods, we discover transcriptomic splicing deregulation typified by differential exon usage. In addition, we discover downregulation of splicing regulator RBFOX2 and CD47 splice isoform upregulation. Importantly, splicing deregulation in pAML induces a therapeutic vulnerability to Rebecsinib in survival, self-renewal, and lentiviral splicing reporter assays. Taken together, the detection and targeting of splicing deregulation represent a potentially clinically tractable strategy for pAML therapy.